How Snake Venom Became the Drug That Saves Millions of Hearts
From a Brazilian pit viper's venom to the most-prescribed cardiovascular drug class in the world — the thirty-year chain that nobody planned and everyone now depends on.
Written by Seth Collins, Pharm.D.
Updated on May 22, 2026
Drug History
3 viewsCaptopril is not the most prescribed drug in the United States, but it may be the most consequential one nobody talks about by name. It belongs to a class called ACE inhibitors, now standard of care for hypertension, heart failure, diabetic nephropathy, and the critical weeks following a heart attack. Tens of millions of people take one every day. The mechanism that makes them work was identified in the venom of a Brazilian pit viper, worked out by a pharmacologist who nearly had his project abandoned, and converted into an oral drug by two chemists at a pharmaceutical company that had already pulled the funding.
The whole chain, from the snake to the pharmacy shelf, took about thirty years. What makes it worth tracing is that none of the steps were obvious from the one before. Each person followed a specific and narrow question, and the answers kept pointing somewhere the original investigator had not intended to go.
The Viper
The snake is Bothrops jararaca. It lives in southeastern Brazil, Argentina, and Paraguay, and it accounts for the majority of snakebite fatalities in Brazil. The venom causes hemorrhage, tissue destruction, and in many victims a rapid collapse of blood pressure that can be fatal before other symptoms become the primary concern.
In the 1940s, a Brazilian physician and pharmacologist named Mauricio Rocha e Silva was investigating the hypotensive component of the venom, trying to characterize why blood pressure dropped so severely in envenomated patients. He found that the venom triggered the release of a peptide from plasma proteins, and that peptide caused blood vessels to dilate. He named it bradykinin, from the Greek for slow movement, based on how it caused smooth muscle to contract. The compound was a potent vasodilator, and Rocha e Silva published the finding.
The finding raised a question he did not answer. Bradykinin existed naturally in the body, where it was degraded quickly and produced only transient effects. The viper's venom was triggering something far more sustained. Rocha e Silva had identified the molecule being released but had not explained why the venom amplified its effects so dramatically and for so long.
Ferreira and the Potentiating Factor
Sergio Ferreira joined Rocha e Silva's laboratory in the early 1960s, twenty-three years old, with the specific aim of answering that question. He began fractionating Bothrops jararaca venom systematically, looking for whatever component was prolonging bradykinin's activity. Normal bradykinin broke down fast. In the presence of viper venom, it did not. His working hypothesis was that something in the venom blocked the enzyme responsible for degrading it.
By 1965, he had isolated a family of small peptides with exactly that property. They extended bradykinin's vasodilatory effect by preventing its enzymatic breakdown. He called them bradykinin-potentiating factors, abbreviated as BPFs, and published the findings, presenting them at conferences including one at the New York Academy of Sciences in 1966. A pharmacologist named John Vane was in the audience. He noted the work and moved on to other problems; he later received the Nobel Prize for separate research on prostaglandins and aspirin. The BPF findings sat in the literature.
Ferreira went to London on a fellowship at the Royal College of Surgeons, then to the United States, where he joined a laboratory at the NIH. He brought purified BPF samples with him. Working with Kevin Erdos at the University of Texas in 1970, he identified the specific enzyme his BPFs were inhibiting: kininase II, which degraded bradykinin by cleaving amino acids from its terminal end. Blocking kininase II allowed bradykinin to accumulate and persist, which explained the venom's sustained hypotensive effect.
What Ferreira did not yet know was that kininase II had already been discovered by a different researcher, in a different city, studying a completely separate biological system, under a different name.
The Renin Connection
In 1954, a biochemist named Leonard Skeggs at the Veterans Administration Hospital in Cleveland was studying the hormonal regulation of blood pressure. He characterized an enzyme that converted an inactive peptide precursor called angiotensin I into its active form, angiotensin II, and he named it angiotensin-converting enzyme, which got abbreviated to ACE.
Angiotensin II is a potent vasoconstrictor. It raises blood pressure by directly tightening blood vessels and simultaneously stimulates release of aldosterone, which drives the kidneys to retain sodium, increasing blood volume and raising pressure further. The system Skeggs was working in, which became known as the renin-angiotensin-aldosterone system, was one of the body's primary mechanisms for elevating and sustaining blood pressure. Skeggs characterized ACE within that system and published the findings. Nobody immediately pursued inhibiting it; blocking a physiologically essential enzyme requires a reason, and the reason was not obvious yet.
The reason became obvious when Ferreira identified kininase II as his target. The two enzymes were the same protein. The enzyme that degraded bradykinin and the enzyme that produced angiotensin II were identical, which meant that Ferreira's viper peptides were doing two things simultaneously: preventing bradykinin from breaking down, and blocking the production of angiotensin II. Both effects reduced blood pressure through independent pathways, and the venom was hitting both at once, which explained why the hypotension it caused was so severe and so sustained.
The implication for drug development was straightforward on paper. A compound that blocked ACE would reduce angiotensin II production, allow bradykinin to persist, and lower blood pressure through two complementary mechanisms unlike anything then available. The question was whether such a compound could be made into something a patient could swallow.
Squibb and the Reluctant Program
In 1968, Ferreira took a fellowship at the Roche Institute of Molecular Biology in Nutley, New Jersey, and began collaborating with researchers at the nearby Squibb pharmaceutical company. He shared his purified BPF peptides. A Squibb pharmacologist named David Cushman and a medicinal chemist named Miguel Ondetti began testing them in hypertensive animal models. The BPFs lowered blood pressure in rats; the mechanism translated across species.
The problem was that the BPFs were peptides, and peptides are digested in the gastrointestinal tract before reaching systemic circulation. There was no viable path to an oral formulation. Injection was possible in principle but not practical for a medication patients would need to take indefinitely. Squibb's management reviewed the program around 1970 and concluded that the probability of developing an orally active ACE inhibitor was too low to justify continued investment. They reduced the resources allocated to the project.
Cushman and Ondetti kept working with what time they had. The core problem was that they needed to design a small, non-peptide molecule that could bind ACE's active site tightly enough to inhibit it, survive oral absorption, and act systemically. To design a molecule that fits a binding site, you need to know the binding site's geometry. ACE had not been crystallized; its three-dimensional structure was unknown.
The Carboxypeptidase Model
The structural information Cushman and Ondetti needed came from a different enzyme. Carboxypeptidase A is a digestive enzyme that cleaves amino acids from the terminal end of protein chains, and its active site had been fully characterized. At the center sat a zinc ion that coordinated with the substrate and facilitated the cleavage reaction. ACE also cleaved terminal amino acids, and the hypothesis, based on mechanistic similarity, was that it had a comparable zinc-dependent active site.
If that was correct, a molecule designed to bind zinc with high affinity, attached to a scaffold shaped to fit the ACE active site as Cushman and Ondetti had modeled it, would block the enzyme without being a peptide. They focused on the sulfhydryl group, which has strong affinity for zinc ions, and began synthesizing compounds built around it. The early candidates were weak inhibitors. They adjusted the scaffold iteratively, modifying the spacer length and geometry between the sulfhydryl and the rest of the molecule based on what the carboxypeptidase structural data implied about ACE's binding pocket.
By 1975, they had a compound designated SQ 14,225. It inhibited ACE potently in enzyme assays, was absorbed after oral administration in rats, and reduced blood pressure in hypertensive animal models. They named it captopril. The synthesis appeared in Science in 1977. The molecule had not been isolated from any biological source; it was designed from structural inference and built in a laboratory. It was among the earliest examples of what would later be called rational drug design, constructing a compound to fit a molecular target based on mechanistic reasoning rather than screening natural products or chemical libraries for incidental activity.
Clinical Trials and the Dosing Problem
Human trials began in the late 1970s. Patients with severe refractory hypertension who had not responded to existing treatments showed meaningful blood pressure reductions. The mechanism that had worked in rats worked in people.
The early trials also used doses that were too high, and the consequences moved quickly into the press. At elevated doses, captopril caused neutropenia and proteinuria, particularly in patients with existing kidney disease who eliminated the drug slowly. By 1980, an FDA advisory committee had recommended restricting the drug to treatment-resistant cases only, and critics argued that Squibb had advanced dosing too aggressively before the safety profile was adequately understood.
Squibb reduced the doses. At lower doses, the neutropenia and proteinuria were rare, because the toxicity was dose-dependent rather than mechanism-dependent. One side effect persisted across the dose range: a dry cough affecting a meaningful proportion of patients. The cough was not a sign of toxicity. It resulted from bradykinin accumulating in airway tissue, a direct consequence of the drug's mechanism. The same bradykinin preservation that lowered blood pressure also irritated airways in susceptible patients. When angiotensin receptor blockers arrived as an alternative class in the 1990s, a portion of ACE inhibitor patients switched. ARBs block angiotensin II at the receptor rather than at the enzyme, so they do not affect bradykinin levels and do not produce the cough.
Captopril received FDA approval for hypertension in 1981. Approval for heart failure followed within three years. The SAVE trial, published in 1992, showed that captopril reduced mortality and morbidity after myocardial infarction in patients with impaired ventricular function. Studies in diabetic nephropathy established that ACE inhibition slowed the progression of kidney disease in diabetic patients beyond what blood pressure reduction alone could explain. Each new indication reflected the same mechanism operating in a different clinical context.
What the Class Became
Captopril's approval created the template. Enalapril followed in 1985, designed as a prodrug that the liver converted to its active form after absorption, with a longer half-life that allowed twice-daily dosing instead of three times daily. Lisinopril came next, then ramipril, whose results in the HOPE trial published in 2000 showed reduced cardiovascular death, myocardial infarction, and stroke in high-risk patients without existing heart failure. That finding substantially broadened the indication for the class. Perindopril, benazepril, fosinopril, and quinapril extended the scaffold further. What Cushman and Ondetti designed in 1975 became an entire pharmacological category.
ACE inhibitors are now on the World Health Organization's Essential Medicines List. Generic lisinopril costs a few dollars a month. The class appears in guidelines across internal medicine, cardiology, nephrology, and endocrinology as a first-line or near-first-line agent depending on indication. Total annual prescriptions for the class in the United States run into the hundreds of millions.
Ferreira, who identified the bradykinin-potentiating factors, established the kininase II mechanism, and brought the biological rationale for ACE inhibition to Squibb, returned to Brazil in the 1970s and spent the rest of his career there. He was not included in the major awards that recognized the captopril work. Cushman and Ondetti received the Albert Lasker Award for Clinical Medical Research in 1999, often described as the American Nobel. The Nobel itself has not been awarded for the ACE inhibitor work.
The Snake at the End
The chain runs from a pharmacologist in Brazil studying why a pit viper's bite collapses blood pressure, to the isolation of peptides that block a degradation enzyme, to the recognition that the enzyme has a second identity and a second function nobody had connected to the first, to two chemists in New Jersey who used an unrelated enzyme's structural data to design a binding site they could not directly observe and built a molecule to fit it. The drug class that came out of that sequence now covers most of the cardiovascular disease spectrum in clinical medicine.
None of the people in that chain were working toward captopril. Rocha e Silva wanted to understand venom toxicity. Ferreira wanted to explain why bradykinin behaved differently in the presence of viper peptides. Skeggs was characterizing a hormone system that regulated blood pressure in the other direction. Cushman and Ondetti were trying to solve an oral delivery problem that their employer had concluded was probably unsolvable. What they collectively produced was one of the more durable drug classes in modern medicine, prescribed to patients on every continent, traceable in a direct and documented line to a snake that continues to kill people in Brazil every year.
Sources
Rocha e Silva M, Beraldo WT, Rosenfeld G. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. American Journal of Physiology. 1949;156(2):261-273.
Ferreira SH. A bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca. British Journal of Pharmacology. 1965;24(1):163-169. doi:10.1111/j.1476-5381.1965.tb01700.x
Skeggs LT, Marsh WH, Kahn JR, Shumway NP. The existence of two forms of hypertensin. Journal of Experimental Medicine. 1954;99(3):275-282.
Erdos EG, Sloane EM. An enzyme in human blood plasma that inactivates bradykinin and kallidins. Biochemical Pharmacology. 1962;11:585-592. Ferreira SH, Bartelt DC, Greene LJ. Isolation of bradykinin-potentiating peptides from Bothrops jararaca venom. Biochemistry. 1970;9(13):2583-2593.
Cushman DW, Cheung HS, Sabo EF, Ondetti MA. Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry. 1977;16(25):5484-5491.
Ondetti MA, Rubin B, Cushman DW. Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science. 1977;196(4288):441-444. doi:10.1126/science.191908
Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. New England Journal of Medicine. 1992;327(10):669-677.
Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. New England Journal of Medicine. 2000;342(3):145-153.
Albert and Mary Lasker Foundation. 1999 Albert Lasker Award for Clinical Medical Research: David Cushman and Miguel Ondetti. Available at: laskerfoundation.org.
Acharya KR, Sturrock ED, Riordan JF, Ehlers MR. Ace revisited: a new target for structure-based drug design. Nature Reviews Drug Discovery. 2003;2(11):891-902. doi:10.1038/nrd1227
The Pillars is a series on the foundational molecules of modern medicine. Written by Seth Collins, Pharm.D.
The whole chain, from the snake to the pharmacy shelf, took about thirty years. What makes it worth tracing is that none of the steps were obvious from the one before. Each person followed a specific and narrow question, and the answers kept pointing somewhere the original investigator had not intended to go.
The Viper
The snake is Bothrops jararaca. It lives in southeastern Brazil, Argentina, and Paraguay, and it accounts for the majority of snakebite fatalities in Brazil. The venom causes hemorrhage, tissue destruction, and in many victims a rapid collapse of blood pressure that can be fatal before other symptoms become the primary concern.
In the 1940s, a Brazilian physician and pharmacologist named Mauricio Rocha e Silva was investigating the hypotensive component of the venom, trying to characterize why blood pressure dropped so severely in envenomated patients. He found that the venom triggered the release of a peptide from plasma proteins, and that peptide caused blood vessels to dilate. He named it bradykinin, from the Greek for slow movement, based on how it caused smooth muscle to contract. The compound was a potent vasodilator, and Rocha e Silva published the finding.
The finding raised a question he did not answer. Bradykinin existed naturally in the body, where it was degraded quickly and produced only transient effects. The viper's venom was triggering something far more sustained. Rocha e Silva had identified the molecule being released but had not explained why the venom amplified its effects so dramatically and for so long.
Ferreira and the Potentiating Factor
Sergio Ferreira joined Rocha e Silva's laboratory in the early 1960s, twenty-three years old, with the specific aim of answering that question. He began fractionating Bothrops jararaca venom systematically, looking for whatever component was prolonging bradykinin's activity. Normal bradykinin broke down fast. In the presence of viper venom, it did not. His working hypothesis was that something in the venom blocked the enzyme responsible for degrading it.
By 1965, he had isolated a family of small peptides with exactly that property. They extended bradykinin's vasodilatory effect by preventing its enzymatic breakdown. He called them bradykinin-potentiating factors, abbreviated as BPFs, and published the findings, presenting them at conferences including one at the New York Academy of Sciences in 1966. A pharmacologist named John Vane was in the audience. He noted the work and moved on to other problems; he later received the Nobel Prize for separate research on prostaglandins and aspirin. The BPF findings sat in the literature.
Ferreira went to London on a fellowship at the Royal College of Surgeons, then to the United States, where he joined a laboratory at the NIH. He brought purified BPF samples with him. Working with Kevin Erdos at the University of Texas in 1970, he identified the specific enzyme his BPFs were inhibiting: kininase II, which degraded bradykinin by cleaving amino acids from its terminal end. Blocking kininase II allowed bradykinin to accumulate and persist, which explained the venom's sustained hypotensive effect.
What Ferreira did not yet know was that kininase II had already been discovered by a different researcher, in a different city, studying a completely separate biological system, under a different name.
The Renin Connection
In 1954, a biochemist named Leonard Skeggs at the Veterans Administration Hospital in Cleveland was studying the hormonal regulation of blood pressure. He characterized an enzyme that converted an inactive peptide precursor called angiotensin I into its active form, angiotensin II, and he named it angiotensin-converting enzyme, which got abbreviated to ACE.
Angiotensin II is a potent vasoconstrictor. It raises blood pressure by directly tightening blood vessels and simultaneously stimulates release of aldosterone, which drives the kidneys to retain sodium, increasing blood volume and raising pressure further. The system Skeggs was working in, which became known as the renin-angiotensin-aldosterone system, was one of the body's primary mechanisms for elevating and sustaining blood pressure. Skeggs characterized ACE within that system and published the findings. Nobody immediately pursued inhibiting it; blocking a physiologically essential enzyme requires a reason, and the reason was not obvious yet.
The reason became obvious when Ferreira identified kininase II as his target. The two enzymes were the same protein. The enzyme that degraded bradykinin and the enzyme that produced angiotensin II were identical, which meant that Ferreira's viper peptides were doing two things simultaneously: preventing bradykinin from breaking down, and blocking the production of angiotensin II. Both effects reduced blood pressure through independent pathways, and the venom was hitting both at once, which explained why the hypotension it caused was so severe and so sustained.
The implication for drug development was straightforward on paper. A compound that blocked ACE would reduce angiotensin II production, allow bradykinin to persist, and lower blood pressure through two complementary mechanisms unlike anything then available. The question was whether such a compound could be made into something a patient could swallow.
Squibb and the Reluctant Program
In 1968, Ferreira took a fellowship at the Roche Institute of Molecular Biology in Nutley, New Jersey, and began collaborating with researchers at the nearby Squibb pharmaceutical company. He shared his purified BPF peptides. A Squibb pharmacologist named David Cushman and a medicinal chemist named Miguel Ondetti began testing them in hypertensive animal models. The BPFs lowered blood pressure in rats; the mechanism translated across species.
The problem was that the BPFs were peptides, and peptides are digested in the gastrointestinal tract before reaching systemic circulation. There was no viable path to an oral formulation. Injection was possible in principle but not practical for a medication patients would need to take indefinitely. Squibb's management reviewed the program around 1970 and concluded that the probability of developing an orally active ACE inhibitor was too low to justify continued investment. They reduced the resources allocated to the project.
Cushman and Ondetti kept working with what time they had. The core problem was that they needed to design a small, non-peptide molecule that could bind ACE's active site tightly enough to inhibit it, survive oral absorption, and act systemically. To design a molecule that fits a binding site, you need to know the binding site's geometry. ACE had not been crystallized; its three-dimensional structure was unknown.
The Carboxypeptidase Model
The structural information Cushman and Ondetti needed came from a different enzyme. Carboxypeptidase A is a digestive enzyme that cleaves amino acids from the terminal end of protein chains, and its active site had been fully characterized. At the center sat a zinc ion that coordinated with the substrate and facilitated the cleavage reaction. ACE also cleaved terminal amino acids, and the hypothesis, based on mechanistic similarity, was that it had a comparable zinc-dependent active site.
If that was correct, a molecule designed to bind zinc with high affinity, attached to a scaffold shaped to fit the ACE active site as Cushman and Ondetti had modeled it, would block the enzyme without being a peptide. They focused on the sulfhydryl group, which has strong affinity for zinc ions, and began synthesizing compounds built around it. The early candidates were weak inhibitors. They adjusted the scaffold iteratively, modifying the spacer length and geometry between the sulfhydryl and the rest of the molecule based on what the carboxypeptidase structural data implied about ACE's binding pocket.
By 1975, they had a compound designated SQ 14,225. It inhibited ACE potently in enzyme assays, was absorbed after oral administration in rats, and reduced blood pressure in hypertensive animal models. They named it captopril. The synthesis appeared in Science in 1977. The molecule had not been isolated from any biological source; it was designed from structural inference and built in a laboratory. It was among the earliest examples of what would later be called rational drug design, constructing a compound to fit a molecular target based on mechanistic reasoning rather than screening natural products or chemical libraries for incidental activity.
Clinical Trials and the Dosing Problem
Human trials began in the late 1970s. Patients with severe refractory hypertension who had not responded to existing treatments showed meaningful blood pressure reductions. The mechanism that had worked in rats worked in people.
The early trials also used doses that were too high, and the consequences moved quickly into the press. At elevated doses, captopril caused neutropenia and proteinuria, particularly in patients with existing kidney disease who eliminated the drug slowly. By 1980, an FDA advisory committee had recommended restricting the drug to treatment-resistant cases only, and critics argued that Squibb had advanced dosing too aggressively before the safety profile was adequately understood.
Squibb reduced the doses. At lower doses, the neutropenia and proteinuria were rare, because the toxicity was dose-dependent rather than mechanism-dependent. One side effect persisted across the dose range: a dry cough affecting a meaningful proportion of patients. The cough was not a sign of toxicity. It resulted from bradykinin accumulating in airway tissue, a direct consequence of the drug's mechanism. The same bradykinin preservation that lowered blood pressure also irritated airways in susceptible patients. When angiotensin receptor blockers arrived as an alternative class in the 1990s, a portion of ACE inhibitor patients switched. ARBs block angiotensin II at the receptor rather than at the enzyme, so they do not affect bradykinin levels and do not produce the cough.
Captopril received FDA approval for hypertension in 1981. Approval for heart failure followed within three years. The SAVE trial, published in 1992, showed that captopril reduced mortality and morbidity after myocardial infarction in patients with impaired ventricular function. Studies in diabetic nephropathy established that ACE inhibition slowed the progression of kidney disease in diabetic patients beyond what blood pressure reduction alone could explain. Each new indication reflected the same mechanism operating in a different clinical context.
What the Class Became
Captopril's approval created the template. Enalapril followed in 1985, designed as a prodrug that the liver converted to its active form after absorption, with a longer half-life that allowed twice-daily dosing instead of three times daily. Lisinopril came next, then ramipril, whose results in the HOPE trial published in 2000 showed reduced cardiovascular death, myocardial infarction, and stroke in high-risk patients without existing heart failure. That finding substantially broadened the indication for the class. Perindopril, benazepril, fosinopril, and quinapril extended the scaffold further. What Cushman and Ondetti designed in 1975 became an entire pharmacological category.
ACE inhibitors are now on the World Health Organization's Essential Medicines List. Generic lisinopril costs a few dollars a month. The class appears in guidelines across internal medicine, cardiology, nephrology, and endocrinology as a first-line or near-first-line agent depending on indication. Total annual prescriptions for the class in the United States run into the hundreds of millions.
Ferreira, who identified the bradykinin-potentiating factors, established the kininase II mechanism, and brought the biological rationale for ACE inhibition to Squibb, returned to Brazil in the 1970s and spent the rest of his career there. He was not included in the major awards that recognized the captopril work. Cushman and Ondetti received the Albert Lasker Award for Clinical Medical Research in 1999, often described as the American Nobel. The Nobel itself has not been awarded for the ACE inhibitor work.
The Snake at the End
The chain runs from a pharmacologist in Brazil studying why a pit viper's bite collapses blood pressure, to the isolation of peptides that block a degradation enzyme, to the recognition that the enzyme has a second identity and a second function nobody had connected to the first, to two chemists in New Jersey who used an unrelated enzyme's structural data to design a binding site they could not directly observe and built a molecule to fit it. The drug class that came out of that sequence now covers most of the cardiovascular disease spectrum in clinical medicine.
None of the people in that chain were working toward captopril. Rocha e Silva wanted to understand venom toxicity. Ferreira wanted to explain why bradykinin behaved differently in the presence of viper peptides. Skeggs was characterizing a hormone system that regulated blood pressure in the other direction. Cushman and Ondetti were trying to solve an oral delivery problem that their employer had concluded was probably unsolvable. What they collectively produced was one of the more durable drug classes in modern medicine, prescribed to patients on every continent, traceable in a direct and documented line to a snake that continues to kill people in Brazil every year.
Sources
Rocha e Silva M, Beraldo WT, Rosenfeld G. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. American Journal of Physiology. 1949;156(2):261-273.
Ferreira SH. A bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca. British Journal of Pharmacology. 1965;24(1):163-169. doi:10.1111/j.1476-5381.1965.tb01700.x
Skeggs LT, Marsh WH, Kahn JR, Shumway NP. The existence of two forms of hypertensin. Journal of Experimental Medicine. 1954;99(3):275-282.
Erdos EG, Sloane EM. An enzyme in human blood plasma that inactivates bradykinin and kallidins. Biochemical Pharmacology. 1962;11:585-592. Ferreira SH, Bartelt DC, Greene LJ. Isolation of bradykinin-potentiating peptides from Bothrops jararaca venom. Biochemistry. 1970;9(13):2583-2593.
Cushman DW, Cheung HS, Sabo EF, Ondetti MA. Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry. 1977;16(25):5484-5491.
Ondetti MA, Rubin B, Cushman DW. Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science. 1977;196(4288):441-444. doi:10.1126/science.191908
Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. New England Journal of Medicine. 1992;327(10):669-677.
Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. New England Journal of Medicine. 2000;342(3):145-153.
Albert and Mary Lasker Foundation. 1999 Albert Lasker Award for Clinical Medical Research: David Cushman and Miguel Ondetti. Available at: laskerfoundation.org.
Acharya KR, Sturrock ED, Riordan JF, Ehlers MR. Ace revisited: a new target for structure-based drug design. Nature Reviews Drug Discovery. 2003;2(11):891-902. doi:10.1038/nrd1227
The Pillars is a series on the foundational molecules of modern medicine. Written by Seth Collins, Pharm.D.
Tags
Issue 003
Drug History
ACE Inhibitors
Pharmacology